Human endogenous retroviruses (HERVs) and elements containing long terminal repeat-like sequences may comprise up to 8% of the human genome. HERVs entered the human genome after fortuitous germ line integration of exogenous retroviruses and were subsequently fixed in the general population. They may have been preserved to ensure genome plasticity and this can provide the host with new functions, such as protection from exogenous viruses and fusiogenic activity (e.g., membrane fusion, exocytosis, or endocytosis). HERVs contain over 200 distinct groups and subgroups. The accumulation of mutations has led to a loss of infectivity of HERVs, and in general they are largely noninfectious retroviral remnants. However, open reading frames (ORFs) have been observed for ERV3, HERV-E 4-1, and HERV-K, but their significance is unknown.
The most biologically active HERVs are members of the HERV-K superfamily which is characterized by the presence of primer binding sites for lysine tRNA. Only HERV-K appears to have the full complement of open reading frames typical of replication competent mammalian retroviruses. The K family contains a central open reading frame (cORF) and is comparable to HIV-1 Rev protein. HERV-K was originally identified by its homology to the mouse mammary tumor virus (MMTV), and is transcriptionally active in several human cancer tissues, including breast cancer tissues, as well as tumor cell lines, such as the human breast cancer cell line T47D and the teratocarcinoma cell line GH.
HERV-K env mRNA is frequently expressed in human breast cancer and HERV-E mRNA is expressed in prostate cancer. Additionally, mRNA from multiple HERV families is transcribed only in ovarian cancer cell lines and tissues. For example, the expression of HERV-K env mRNA was greater in ovarian epithelial tumors than it was in normal ovarian tissues (N=254).
Breast cancer is a significant health problem for women in the United States and throughout the world. Although advances have been made in detection and treatment of the disease, breast cancer remains the second leading cause of cancer-related deaths in women, affecting more than 180,000 women in the United States each year. For women in North America, the life-time odds of getting breast cancer are now one in eight.
No vaccine or other universally successful method for the prevention or treatment of breast cancer is currently available. Management of the disease currently relies on a combination of early diagnosis (through routine screening procedures) and aggressive treatment, which may include one or more of a variety of treatments such as surgery, radiotherapy, chemotherapy, and hormone therapy. The course of treatment for a particular breast cancer is often selected based on a variety of prognostic parameters, including an analysis of specific-tumor markers. See, e.g., Porter-Jordan & Lippman, Breast Cancer 8:73-100, 1994. However, the use of established markers often leads to a result that is difficult to interpret, and the high mortality observed in breast cancer patients indicates that improvements are needed in the treatment, diagnosis, and prevention of the disease.
Ovarian cancer is another leading cause of cancer deaths among women and has the highest mortality of any of the gynecologic cancers. Symptoms usually do not become apparent until the tumor compresses or invades adjacent structures, or ascites develops, or metastases become clinically evident. As a result, two thirds of women with ovarian cancer have advanced (Stage III or IV) disease at the time of diagnosis.
Potential screening tests for ovarian cancer include the bimanual pelvic examination, the Papanicolaou (Pap) smear, tumor markers, and ultrasound imaging. The pelvic examination, which can detect a variety of gynecologic disorders, is of unknown sensitivity in detecting ovarian cancer. Although pelvic examinations can occasionally detect ovarian cancer, small, early-stage ovarian tumors are often not detected by palpation due to the deep anatomic location of the ovary. Thus, ovarian cancers detected by pelvic examination are generally advanced and associated with poor survival. The pelvic examination may also produce false positives when benign adnexal masses (e.g., functional cysts) are found. The Pap smear may occasionally reveal malignant ovarian cells, but it is not considered to be a valid screening test for ovarian carcinoma. Ultrasound imaging has also been evaluated as a screening test for ovarian cancer, since it is able to estimate ovarian size, detect masses as small as 1 cm, and distinguish solid lesions from cysts.
Serum tumor markers are often elevated in women with ovarian cancer. Examples of these markers include carcinoembryonic antigen, ovarian cystadenocarcinoma antigen, lipid-associated sialic acid, NB/70K, TAG 72.3, CAI 15-3, and CA-125, respectively. Evidence is limited on whether tumor markers become elevated early enough in the natural history of occult ovarian cancer to provide adequate sensitivity for screening, and tumor markers may have limited specificity.
Tumor-associated antigens recognized by the immune system are a very attractive target for human cancer diagnostics and therapy. However, few immunotherapy approaches have been used for the treatment and prevention of cancers. One problem limiting the success of cancer vaccines is that the immune system generally does not recognize cancer cells as being foreign, which is a requirement for initiating an immune response. Cancer immunotherapy, however, is limited due in part to the limited number of tumor-associated antigens identified to date.